Quinazolinedione derivatives



United States Patent 3,274,194 QUINAZOLINEDIONE DERIVATIVES Shin Hayao,Ellrhart, 11:11., assignor to Miles Laboratories, Inc., Elkhart, Ind., acorporation of Indiana No Drawing. Filed Mar. 29, 1963, Ser. No. 269,1686 Claims. (Cl. 260-2564) This invention relates to novelquinazolinedione derivatives. In one of its more particular aspects thisinvention relates to 3 substituted 2,4(lH,3H)-quinazolinediones and tonovel methods for the preparation thereof.

The quinazolinedione derivatives of the invention may be represented bythe following general formula:

In this formula R represents one or more groups such as hydrogen,halogen, lower alkyl, lower alkoxy, nitro and amino, n equals 0 to 6inclusive and R represents di-lower alkylamino or a heterocyclicradical. The heterocyclic radical may be substituted or unsubstitutedand may contain one or more heterocyclic nitrogen atoms. For example, inan especially preferred sub-group of compounds, R may represent4-aryl-1-piperazyl and the corresponding radicals in which aryl is asubstituted phenyl radical.

The compounds of this invention may be conveniently prepared by reactingthe corresponding o-aminobenzamides in a suitable solvent with phosgeneor with ethyl chloroformate. The o-amino'benzamides used as the startingmaterials may be conveniently prepared from a primary amine and isatoicanhydride or a substituted derivative thereof. These preparations may beillustrated by means of the'following sequence of equations:

\ ClCOO CIHIS NHC O O C2H "ice benzene as the solvent. Other solventswhich may be used for this purpose include, for example, acetic acid.

The carbethoxylation of the primary aromatic amino group may be readilyaccomplished by reaction of the benzamide with ethyl chloroformatefollowed by heating the resulting ethoxycarbamoyl salt to a temperatureabove its melting point to effect cyclization to the desiredquinazolinedione. For the carbethoxylation the use of a suitable solventfor the benzamide such as chlorobenzene is recommended. Other solventswhich may be used include tetrahydro furan and chloroform, for example.The quinazolinediones prepared according to the foregoing reactionscheme may be isolated as crystalline salts such as the hydrochloridesor other suitable acid salts.

The compounds of this invention are useful as antiinflammatory agentsand sedatives.

This invention will be better understood by reference to the followingexamples which are included for purposes of illustration and are not tobe construed as in any way limiting the scope of this invention which isdefined in the claims appended hereto.

EXAMPLE 1 3- (4-phenyl-I -piperazyl -2,4 (1 H ,3H -quinaz0linedi0ne A.1- o-AMIN OBENZA'MIDO -4-PHENYLPIPERAZIN E A mixture ofl-amino-4-phenylpiperazine (63.5 g., 0.39 mole) and isatoic anhydride(58.1 g., 0.39 mole) gave a brown liquid with evolution of carbondioxide and then became a solid mass in a few minutes. It was heated ona steam bath for an hour and the light tan solid was recrystallized fromaqueous dimethylformamide (DMF) and decolorized with charcoal to give alight tan crystalline solid which was collected by suction and washedwith ether, yield 79.7 g. (69.1%), M.P. 202203. A sample wasrecrystallized from aqueous DMF to give a buffcolored solid of M.P.201-203". (Note: All temperatures are expressed as degrees centigradeunless otherwise indicated.)

Analysis.Calcd. for C I-I N O: N, 18.9. Found: N, 19.2.

B. 3-(4-PHENYL-1-PIPERAZYL)-2,4(1H,3H)-QUINAZO-LINEDIONE-DIHYDROCHLORIDE To a boiling solution ofl-(o-aminobenzamido)-4-phenylpiperazine (29.6 g., 0.1 mole) in 250 ml.of chlorobenzene was introduced a slow stream of phosgene with vigorousstirring during 45 minutes to give a light tan gummy solid. The reactionmixture was cooled in an ice-water bath and the solid was collected on afilter. It was washed with ethyl acetate and dried in air, yield 37.6g., M.P. 250-260 (dec.), darkening beginning at ca. 240. It wassuspended in aqueous methanolic DMF and dry hydrogen chloride wasbubbled in to give a clear solution which was filtered and againsaturated with dry hydrogen chloride to cause separation of a colorlesssolid. Ethyl acetate was added to the hot mixture and the solid wascollected by suction, yield 24.0 g., M.P. 260.

Analysis.Ca'lcd. for C H N O 2HCl: N, Found: N, 14.2.

EXAMPLE 2 3-(2-pyrzdyl)-2,4 (1 H,3H -quinazolinedi0ne A. 3- (2-PYRIDYL)-2,4(1H,3H) -QUINAZOLINEDIONE 3 27 4, 1 9 4 3 4 water bath. The yellowsolid was broken up and collected EXAMPLE 4 on a filter, yield 56.7 g.,M.P. 210-220. It was dissolved in hot aqueous methanol and saturatedwith dry hydrogen chloride to give a pale yellow solid which wascollected, washed wits ethyl acetate and dried in air, yield 48.0 g.,M.P. 220 2 25". It was recrystallized again to give a colorless solid ofM.P. 215,219 (dec.), yield 44.2 g. It was dissolved in water and madebasic with ammonium hydroxide to give a colorless solid of M.P. 180-200,yield 33.2 g. It was recrystallized from aqueous DMF- methanol to give alight tan crystalline solid of M.P. 132-134, yield 12.0 g. (22.5%recovery of the starting material). The mother liquor was evaporated todryness in vacuo to give a colorless solid mass which was recrystallizedfrom aqueous DMF to give a crystalline solid of M.P. 260, yield 16.8 g.(28% KCl mux.

1750 and 1680 cm.- (imide carbonyls), no amide II band.

Analysis.Calcd. for C H N O N, 17.6. Found: N, 17.6. i

B. 3-(2-PYRIDYL) -2,4-(1H,3H) -QUINAZOLINEDIONE HYDRO'CHLO RIDE The freebase was dissolved in hot methanol-DMF and then saturated with dryhydrogen chloride to give a hot clear solution which was diluted withether to give a colorless hydrochloride of M.P. 260", yield 14.4 g.

Analysis.Calcd. for C H ClN O HCl, 13.2. Found: HCl, 13.0.

EXAMPLE 3 3- [2- (4-phenyl-I-piperazyl) ethyl] 2,4 (1H,3H)-qua'nazolinedione A. 1- [2 (o-AMINOBENZAMIDO ETHYL -4- PHEN YLPIPERAZINE A mixture of 1-(2 aminoethyl) 4-phenylpiperazine (41.0 g., 0.2 mole)and isatoic anhydride (29.8 g., 0.2 mole) was heated on a steam bath foran hour to give a sol-id mass. It was recrystallized from aqueous DMF(carbon) to give a light tan solid of M.P. 139142, yield 51.2 g. (79%).A sample was twice recrystallized from aqueous acetone to give shinyplates of M.P. 141-142.

Analysis.-Calcd. for C H N O: N, 17.3. N, 17.5.

B. 3- [2- (l-PHENYL-l-PIPERAZYL) E'IHYL] -2,4 (1H,3H) QUINAZOLINEDIONEHYDROCHLORIDE Found:

Analysis.Calcd. for C H ClN O N, 14.5. Found: N, 14.5.

C. 3- [2- l-PHENYL-l-PIPERAZYL) ETHYL] 2,4(1H,3H)-QUINAZOLINEDIONE Thefiltrate was concentrated in vacuo to leave a dark brown syrup whichsolidified on cooling. It was treated with sodium hydroxide solution togive a light tan gum which slowly solidified. It was recrystallizedthree times from aqueous DMF to give a pure free base of M.P. 240-243".

Analysia-Calcd. for C I-1 N N, 16.0. Found: N, 16.0.

3- [3-(4-phenyl-1-piperazyl) pr0pyl]- 2,4 (1H,3H -quinazolinedi0ne A.l-PHENYL-l- 3- o-AMINOBENZAMIDO) PROPYL] PIPERAZINE A mixture of1-(3-aminopropyl)-4-phenylpiperazine (67.5 g., 0.31 mole) and isatoicanhydride (50.3 g., 0.31 mole) was heated at ZOO-210 in a wax bath for 3hours to give a dark melt which solidified on standing. It was distilledto give a light amber viscous liquid of B.P. 240-269 (0.7-0.32 mm.),yield 96.8 g. (92.8%). It was dissolved in hot methanol and water wasadded to give an oil which soon solidified on seeding and scratching. Itwas recrystallized from aqueous ethanol to give an analytical sample ofM.P. 121-123".

Analysis.--Calcd. for C H N O: N, 16.6. Found: N, 16.5, 16.6.

B. 3-[3-(4 PHENYL-l-PIPERAZYL)PROPYL]-2,4(1H,3H)- %gg%%ZOLINEDIONEDIHYDROCHLORIDE MONOHY- To a boiling solution of the above amine (33.8g., 0.1 mole) in 300 ml. of chlorobenzene was bubbled in phosgene withvigorous stirring for 30 min. The solution became cloudy in 5 min. and aheavy gum separated. The reaction mixture was cooled in an ice-waterbath .and the gum solidified. It was collected on a filter, washed withethyl acetate-ether to give a colorless solid of M.P. 230- 237 (dec.)with softening at 225, yield 32.5 g. It was dissolved in aqueousmethanol and saturated with dry hydrogen chloride. Ether was added togive a colorless solid of M.P. 225232, yield 23.8 g. It wasrecrystallized again in the same manner to give a pure salt of M.P.224226 (dec.) with softening at 196 and resolidified, yield 18.2 g.

Analysis.-Calcd. for C H N O 2HCLH O: N, 2.3; HCl, 16.0. Found: N, 12.2;HCl, 16.0.

C. 3[3(l-PHENYIrl-PIPERAZYL)PROPYL]- 2,4(1H,3H)-QUINA.ZOLINEDIONE Fivegrams of the above salt was converted to the free base andrecrystallized from aqueous DMF to give a colorless solid of M.P.202-203.

KCl max.

1720 and 1660 cm. (imide carbonyls).

Analysis.-Calcd. for C H N O C, 69.3; H, 6.60; N, 15.4. Found: C, 68.8;H, 6.96; N, 15.4, 15.6.

D. 1- 3- (o-CARBETHOXYAMINOBENZAMIDO PROPYL] -4- PHENYL P-IPERAZINEDIHYDRO CHLORIDE To a boiling solution of1-phenyl-4-[3-(o-aminobenzamido)propyl]piperazine (20.3 g., 0.06 mole)in ml. of chlorobenzene was added dropwise a solution of ethylchloroacetate (6.5 g., 0.06 mole) in 50 ml. of chlorobenzene during 10minutes to give a light amber solution. It was refluxed with stirringfor 1.5 hours and kept at room temperature overnight. The solvent wasremoved in vacuo to leave a dark reddish brown syrup. It was dissolvedin hot methanol and saturated with dry hydrogen chloride. Ethyl acetatewas added to give a solid of MP. 201203 (dec.), yield 25.0 g. It wasonce recrystallized from aqueous methanolic hydrogen chlorideethylacetate to give a colorless solid of M.P. 203204 (dec.), yield 21.0 g.,

heated at 220230 for 3 hours in a wax bath to give a dark brown melt. Itwas dissolved in aqueous methanol, heated with charcoal and treated withdry hydrogen chloride. The hot solution was diluted with ethyl acetateto give a light yellow solid of M.P. 187-188 (dec.), yield 16.6 g. Itwas recrystallized from aqueous methanolic hydrogen chloride-ethylacetate to give a pale yellow solid of M.P. 223-233 with softening at183187, yield 14.2 g. The LR. spectrum (KCl disc) was identical with theone obtained in B above.

Analysis.-Calcd. for C21H2 Cl N4O2H2O: Found: HCl, 16.1.

F. 3-[3-(4-PHENYL-1-PIPERAZYL)PRoPYL]-2,4(1H,3H)-

QUINAZOLINEDIONE The free base was obtained and it melted at 192-194",yield 12.1 g. It was recrystallized from aqueous DMF (charcoal) to givea crystalline solid of M.P. 20 2-203", yield 6.7 g. The mixed M.P. withan authentic sample (from C above) was not depressed.

EXAMPLE 3- [3-(4-0-chl0r0phenyl-1 -piperazyl propyl] -2,4 (1H,3Hquinazolinedione A. 10CHLOROPHENYLA- [3- o-AMINOBENZAMIDO) PROPYL]P-IPERAZINE A mixture of 1-(3-aminopropyl)-4-o-chlorophenylpiperazine(56.4 g., 0.22 mole) and isatoic anhydride (36.3 g., 0.22 mole) washeated on a steam bath for 5 hours. The dark viscous syrup was dissolvedin 2-propanol, saturated with dry hydrogen chloride and diluted withethyl acetate and ether to give 70 g. of crude hydrochloride. It wasrecrystallized from methanolic hydrogen chlorideethyl acetate to give57.6 g. of the hydrochloride. It was converted to the free base,extracted with chloroform and dried over anhydrous magnesium sulfate.The extract was stripped oif the solvent and the remaining syrup wasused for subsequent reaction without purification.

B. 3*[3- (4-o-CHLOROPHENYL-1-PIPERAZYL)PROPYL]-2,4(1H,3H)-QUINAZOLINEDIONE HYDROCHLORIDE To a boiling solution of theabove amine (43.5 g., 0.117 mole) in 250 ml. of chlorobenzene wasintroduced a slow stream of phosgene during 60 min. with vigorousstirring to give a light tan solid mass. It was collected by suction,washed with ethyl acetate-ether and dried in air, yield 48.0 g., M.P.265269 (dec.). It was recrystaL lized from aqueous ethanol-ethyl acetate(charcoal) to give a light buff colored solid of M.P. 260, yield 39.0 g.

Analysis.Calcd. Found: HCl, 8.48.

for C21H24Cl2N402: 8.40-

EXAMPLE 6 3- [3- (4 -m-ch lorophenyl-I -piperazyl) propyl] -2,4- (1H,3H)-quinazolinea'i0ne A. 1- 3- (o-AMINOBENZAMIDO PROPYL] 4-m-CHLOROPHENYLPIPERAZINE B. 3-[3 (km-CHLOROPHENYL 1 PIPERAZYL)PROPYL]-2,4(1H,3H)-QUINAZOLINEDIONE DIHYDROCHLORIDE MONOHYDRATE To a boilingsolution of the above amine (29.8 g., 0.08 mole) in 250 ml. ofchlorobenzene was bubbled in phosgene during 60 min. to give a lightcream colored solid which separated from the hot solution. The reactionmixture was cooled and the solid was collected on a filter, washed withethyl acetate-ether and dried in air, yield 38.1 g., M.P. 239-240". Itwas dissolved in aqueous dimethylformamide-methanol, treated with dryhydrogen chloride and diluted with ethyl acetate-ether to give acolorless solid of M.P. 233234 (bubbling at yield 16.7 g.

Analysis.Calcd. for C H ClN O -2HCl-H O: HCl, 14.9. Found: HCl, 14.7.

C. 3-[3- (4-m-CHLOROPHENYL-l-PIPERAZYL) -PROPYL] The filtrate wasconcentrated in vacuo to leave a white solid separated from the hotsolution, yield 17.7 g., M.P. 234236 (dec.). It was treated with sodiumhydroxide solution to give a gum which slowly solidified. It wascollected on a filter and dried in air, yield 15.6 g., M.P. 190195. Itwas once recrystallized from aqueous DMF to give a colorless solid ofM.P. -196.

1710 and 1670 cm. (imide carbonyls), no amide II band.

Analysis.Calcd. for C H ClN O C, 63.3; H, 5.76; N, 14.0. Found: C, 63.3;H, 6.17; N, 14.2.

EXAMPLE 7 3-[3-(4-phenethyZ-1-piperazyl)pr0pyl] -2,4- (1H,3H)-quinazolinedione A. 1-PI-IENETI-IYL-4- 3-(0-AMINOBENZAMIDO PROPYL]PIPERAZINE TRIHYDROCHLORIDE A mixture of1-phenethyl-4-(3-aminopropyl)piperazine (36.1 g., 0.146 mole) andisatoic anhydride (21.8 g., 0.146 mole) was kept at room temperatureovernight after the initial reaction subsided. The dark solid wasdissolved in hot methanol and saturated with dry hydrogen chloride.Ethyl acetate was added to give a light buff colored solid onscratching, yield 46.4 g., M.P. 264- 266 (dec.). A sample wasrecrystallized from aqueous methanol-ethyl acetate to give a light buficolored solid of M.P. 250".

Analysis.-Calcd. for C H N O'3HCI: HCl, 23.0. Found: HCl, 22.6.

B. 1-PHENETHYL-4-[3 (o-AMINOBENZAMIDO) PROPYLJPIPERAZINE Thehydrochloride was treated with sodium hydroxide solution to give a freebase of M.P. 112113, yield 31.4 g. It was once recrystallized fromaqueous methanol and dried in an oven at 75, yield 25.0 g., M.P. 1121l3.From the filtrate another 5.0 g. of the product was obtained, M.P.111112 The first crop was analyzed.

Analysis.Calcd. for C H N O: N, 15.3. Found N, 15.5.

C. 3- [3- (4-PHENETHYL-1-PIPERAZYL) PROPYL] -2,4- (1H,3H)-QUINAZOLINEDIONE HYDROCHLORIDE D. 3-[3-(4-PHENETHYL-1-PIPERAZYL)PROPYL]-2,4- (1H,3H) -QUINAZOLINEDIONE Theabove hydrochloride (9.5 g.) was converted to free base with sodiumhydroxide solution and the oily free base soon solidified, yield 7.0 g.It was recrystallized from aqueous DMF to give a colorless solid of M.P.166-167.

ouch max.

3390 cm.- (N-H), 1720 and 1670 cm? (imide carbonyls), no amide II band.

A nalysis.Calcd. for C H N O N, 14.3 Found: N, 14.5.

EXAMPLE 8 3- [3-(4-phenyl-1-piperidyl) propyl] -2,4(1H,3H)quinazolinedione A. 1- 3- (o-AMINOBENZAMIDO PROPYL] -4- PHENYLPIPERIDINEA mixture of 1-(3-aminopropyl)-4-phenylpiperidine (38.8 g., 0.178 mole)and isatoic anhydride (29.0 g., 0.178 mole) was heated on a steam bathfor an hour to give a dark semi-solid.

B. 3-[3-( L-PHENYIrl-PIPERIDYL)PROPYL]-2,4-

(1H,3H)-QUINAZOLINEDIONE The dark semi-solid was dissolved in 150 ml. ofchlorobenzene and reacted with a slow stream of phosgene at the boilingpoint of the solvent during 60 minutes to give a dark oil whichseparated from the hot solution. After standing overnight at roomtemperature the resulting dark semi-solid was treated with aqueoussodium hydroxide-chloroform and the aqueous layer was extracted withethyl acetate. The combined extracts were dried quickly while they werestill warm and filtered. The solution gave 20.1 g. of the free base oncooling as a first crop, M.P. 168472". The mother liquor gave a secondcrop on cooling in an ice-water bath, M.P. 166-168", yield 10.2 g. Thecombined solids were recrystallized from aqueous DMF to give a light tansolid of M.P. 168-175, yield 23.8 g. The second recrystallization gave apure product of M.P. 172-176", yield 21.9 g.

KCl rnux.

1720 and 1650 cm." (imide carbonyls), no amide II band.

Analysis.Calcd. for C H N O N, 11.6. Found; N, 11.9. a

c. 3- [3- (l-PHENYL-l-PIPERIDYL) PROPYL] -2,4(1H,3H QUINAZOLINEDIONElllALEA'lE The free base (21.5 g., 0.06 mole) was suspended in ethylacetate and reacted with maleic acid (6.95 g., 0.06 mole) to give acolorless powder of M.P. 192194 (dec.), yield 27.0 g. It wasrecrystallized from methanol-ethyl acetate-ether to give a pure maleateof M.P. 201-202 (dec.), yield 20.7 g.

1720 and 1660 cm. (imide carbonyls), no amide II band.

AULZZYSiSr-CfilCd. for C22H25N302-C4H4041 C, 65.2; H, 6.05; N, 8.77.Found: C, 65.0; H, 5.66; N, 8.88.

EXAMPLE 9 3-(3-diethylaminopropyl)-2,4(1H,3H) quinazolinedionehydrochloride.

A mixture of 3-diethylaminopropylamine (65.2 g., 0.4 mole) and isatoicanhydride (52.0 g., 0.4 mole) gave a dark syrup with evolution of carbondioxide. It was heated on a steam bath'for an hour and set asideovernight. It was dissolved in 200 m1. of chlorobenzene and a slowstream of phosgene was introduced at the boiling point of the solventduring 2 hours to give a dark oil. Ethyl acetate was added and themixture was cooled in an ice-water bath to give a light tan solid ofM.P. 211-214, yield 124.8 g. It was twice recrystallized from methanolto give a little solvated solid which was dried in vacuo in adesiccator, yield 87.3 g., M.P. 227- 228".

Analysis.Calcd. for C H ClN O C, 57.7; H, 7.06; N, 13.5. Found: C, 58.0;H, 7.62; N, 13.7.

EXAMPLE 10 3-[6-(4-phenyl-1-piperazyl) hexyl] -2,4(1H,3H)quinazolinedione A. 1-IHENYL-4- 6 (o-AMINOBENZAMIDO HEXYL] PIPERAZINE Amixture of 1-phenyl-4-(6-aminohexyl)piperazine (68.1 g., 0.261 mole) andisatoic anhydride (42.5 g., 0.261 mole) was heated on a steam bath for 3hours to give a dark melt. It was dissolved in 200 ml. of hot methanoland added to 250 ml. of Z-propanol saturated with hydrogen chloride(86.6 g., 2.36 mole) to give a dark hot solution. It was diluted withethyl acetate and cooled in an ice-water bath to give a light tan solidwhich was collected on a filter and dried in vacuo in a desiccator,yield 127.6 g. (99%). It was suspended in water and treated with sodiumhydroxide solution to give a light tan solid. It was three timesrecrystallized from aqueous DMF to give a light tan crystalline solid ofM.P. 83-91", yield 66.5 g. A sample was recrystallized twice more fromaqueous DMF to give an analytical sample of M.P. 98- 10l.

C1101; max.

3450 and 3330 cm. (NH and NH 1640 crn.- (amide 0 0), 1520 and 1500 cm.(amide II).

Analysis.Calcd. for C H N O: N, 14.7. Found: N, 15.1.

B. 3-[6- (4-PHENYL-1-PIPER.AZYL) HEXYL]-2,4 (1H,3H) QUINAZOLINEDIONEHYDROCHLORIDE To a boiling solution of the above amine (47.9 g., 0.126mole) in 250 ml. of chlorobenzene was bubbled in a slow stream ofphosgene during 60 min. with vigorous stirring to give a light tan solidfrom the hot solution. The reaction mixture was cooled in an ice-waterbath and the solid product was collected on a filter, washed with ethylacetate and dried in air, yield 55.5 g., M.P. 256- 259.v It wasrecrystallized from aqueous methanol- DMF containing hydrogen chlorideto give a slightly bulf colored solid of M.P. 231234, yield 46.5 g. Itwas again recrystallized in the same way to give a product melting at259261 (dec.) with softening at 226, yield 32.1 g.

Analysis.Calcd. for C I-I ClN O- N, 8.25; H, 12.7. Found: N, 8.40; HCl,13.0.

Example 11 3-(3-pyridylmethyl)-2,4(1H,3H)-quinaz0linedi0ne A.3-(o-AMINOBENZAMIDOMETHYL) PYRIDINE To a boiling solution of the aboveamine (51.1 g.,

i 0.248 mole) in 400 ml. of chlorobenzene was introduced a slow streamof phosgene during 30 minutes with stirring to give a yellowish tansolid which came out from the hot solution and made stirring impossible.The reaction mixture was cooled down to room temperature andchlorobenzene was decanted off. The solid was dissolved in hot methanol(charcoal) and diluted with ethyl acetate to give a crystallinehydrochloride of M.P. 229- 232 (dec.), yield 29.9 g. (41.5%). One morerecrystallization gave a solid of M.P. 238 (dec.) with softening at221-224, yield 26.8 g. It was dissolved in water and made basic withconcentrated ammonium hydroxide to give a white gum which soonsolidified on scratching, yield 21.9 g. It was recrystallized fromaqueous DMF to give a colorless powder of M.P. 238- 239", yield 15.0 g.

1720 and 1670 cm? (imide carbonyls), no amide II.

Analysis.Calcd. for C H N O N, 16.6. Found: N, 16.7.

C. 3- (S-PYRIDYLMETHYL)-2,4(1H,3H) -QUINAZOLINE- DIONE HYDROCHLORIDE Thefree base (13.8 g.) was suspended in methanol and treated with dryhydrogen chloride to give a hot clear solution which was diluted withethyl acetate to obtain a colorless flulfy solid of M.P. 245-247", yield13.0 g.

1710 and 1660 cm." (imide carbonyls), no amide H.

Analysis.Calcd. for C H CIN O N (basic), 4.83; HCl, 12.7. Found: N(basic), 4.72; MCl, 12.3.

Example 12 3-[5-(4-phenyl-1piperazyl)pentyl] -2,4(1H,3H)quinazolinedione A. 1-[5- (o-AMINOBENZAMIDO)PENTYL1-4- PHENYLPIPERAZINEA mixture of isatoic anhydride (31.7 g., 0.194 mole) and4-phenyl1-l(5-aminopentyl)piperazine (48.0 g., 0.194 mole) was heated ona steam bath for 1 hour. The solid product was thrice recrystallizedfrom aqueous methanol (charcoal) to give a solid of M.P. 1l2116.

AnaZysis.-Calcd. for C H N O: N, 15.3. Found: N, 15.9.

B. 3-[5-(4-PHENYL-LPIPERAZYL)PENTYL] -2,4(1H,3H)-

QUINAZOLINEDIONE DIHYDROCHLORIDE I C. 3- 5- (4-PHENYL-l-PIPERAZYL)PENTYL] -2,4-

(1H,3H) -QUINAZOLINEDIONE The hydrochloride (5.0 g.) was treated withconcentrated ammonium hydroxide to give a free base melting at l69l73.It was once recrystallized from aqueous acetone-DMF to give a colorlesscrystalline solid of M.P. 172-173".

1720 and 1670 cm.- (imide carbonyls), no amide II band.

Analysis.Calcd. for C23H28N4OZZ N, 14.3. N, 14.2.

Found:

1 0 Example 13 3- [4- (4-phenyl-1-piperazyl) butyl] -2,4(1H,3H)quinazolinedione A. 1-[4-(0AMINOBENZAMIDO) BUTYL1-4- PHENYLPIPERAZINE Amixture of 1-phenyl-4-(4-aminobutyl)piperazine (24.8 g., 0.107 mole) andisatoic anhydride (17.4 g., 0.107 mole) was heated on a steam bathovernight and the resulting solid mass was recrystallized from aqueousacetone to give a pale yellow solid of M.P. 107-110, yield 26.2 g.(69.9%).

B. 3- t (4-PHENYL-1-PIPERAZYL) BUTYL] -2,4 (111,311)

QUINAZOLINEDIONE To a boiling solution of the above amine (26.2 g.,0.0754 mole) in ml. of chlorobenzene was bubbled in a slow stream ofphosgene during 30 minutes to give a light tan solid, yield 35.8 g.,M.P. 270274 (dec.). It was treated with concentrated ammonium hydroxideto give a free base which was recrystallized from aqueous acetone-DMF togive 22.9 g. of a solid melting at 198. It was again recrystallized fromaqueous DMF to give a slightly tan solid of M.P. 196.5197.5.

KCl min.

1720 and 1660 cm (imide carbonyls).

Analysis.Calcd. for C H N O C, 69.9; H, 6.88; N, 14.8. Found: C, 70.1;H, 6.99; N, 15.0.

C. 3-[4-(4-PHENYL-1-PIPERAZYL)BUTYL]-2,4(1H,3H)-

QUINAZOLINEDIONE DIHYDROCHLORIDE The free base was suspended in hotmethanol and treated with dry hydrogen chloride. Enough water was addeduntil all the solid dissolved. Ethyl acetate was added to the hotsolution to give a solid of M.P. 276-277 (dark melt), yield 20.9 g. Y

Analysis.Calcd. for C H Cl N O N (basic), 3.11; HCl, 16.2. Found: N(basic), 3.11; HCl, 16.1.

EXAMPLE 14 3 -[3 -(4 -pheny l-1 -piperazyl propyl -6-ch loro- 2,4(1H,3H) -quinazolinedione- A. 3- [3- (4-PHENYL-1-PIPERAZYL)PROPYL]-6-CHLORO- 2,4 (1H,3H)-QUINAZOLINEDIONE A mixture of1-(3-aminopropyl)-4-phenylpiperazine (30.0 g., 0.14 mole), and6-chloroisatoic anhydride (27.5 g., 0.14 mole) was heated on a steambath for an hour and dissolved in hot methanol-chloroform. The productwas obtained when the solution was cooled and it melted at 143-448",yield 44.0 g. A suspension of the solid (44 g.) in 250 ml. of boilingchlorobenzene was treated with phosgene during an hour to give an oilymaterial which separated from the hot reaction mixture. It crystallizedwhen cooled and was collected by suction. The free base was obtainedwhen the hydrochloride was treated with sodium hydroxide solution andwas recrystallized twice from aqueous methanol to give thequinazolinedione of M.P. 227230, yield 41.0 g. (71.4%

Analysis.Calcd. for C H ClN O N, 14.0. Found: N, 13.7.

B. 3-[3- (4-PHENYL-1-PIPERAZYL) PROPYL1-6-CHLORO-2,4(1H,3H)-QUINAZOLINEDIONE MALEATE To the above product (30.0 g., 0.075mole) was added a solution of maleic acid (8.7 g., 0.075 mole) in 30 ml.of methanol and the resulting solution was heated on a steam bath for afew minutes and then cooled in an ice- Water bath to give the maleatewhich was collected by suction and was recrystallized twice from aqueousmethanol, M.P. 213-216.

Analysis.Calcd. fOI' C21H23CIN4OZ'C4H4O4 N, 10.9; N (basic), 2.73.Found: N, 10.7; N (basic), 2.76.

1 1 EXAMPLE 1s 3-[4-(4-phenyl-1-piperazyl) butyl1-6-chloro- 2,4 (1H,3H)-quinazlinea'i0ne maleate A mixture of 1 (4 aminobutyl) 4phenylpiperazine (20.0 g., 0.085 mole) and 6-chloroisatoic anhydride(10.7 g., 0.085 mole) was heated on a steam bath for an hour. The solidmass was dissolved in hot methanol and diluted with ether to give acrude product; 1-[4-(2'-amino-5-chlorobenzamido)butyl]-4-phenylpiperazine. It was dissolved in boilingchlorobenzene (250 ml.) and treated with a slow stream of phosgene foran hour. A thick oil separated out which solidified upon cooling. Thehydrochloride was shaken with a mixture of 20% sodium hydroxide solutionand chloroform and the insoluble solid was collected by suction. It wasrecrystallized from aqueous methanol to give 10 g. (30% yield) of thequinazolinedi-one, M.P. 210215. It was converted to the maleate andrecrystallized to give 2.0 g. of the pure maleate of M.P. 227229.

Analysis.Calcd. for C H ClN O N, 10.6; N (basic), 2.65. Found: N, 10.4;N (basic), 2.65.

EXAMPLE 16 A. 3- (l-PHENYL-l-PIPERAZYL) PENTYL] -6-CI-ILO RO-'2,4(1H,3H)-QUINAZOLINEDIONE A mixture of 6-chloroisatoic anhydride(30.0 g., 0.15 mole) and 1-(5-aminopentyl)-4-phenylpiperazine (37.0 g.,0.15 mole) was heated on a steam bath for an hour and the resultingsolid mass was dissolved in hot methanol. The solution was diluted withether to precipitate a crude 1 [5 (2 amino 5 chlorobenzamido)pentyl] 4-phenylpiperazine which was recrystallized from methanol-ether to give 32g. of the product melting at 115- 120. It was dissolved in 500 ml. ofboiling chlorobenzene and phosgene was introduced slowly during an hour.The reaction mixture was cooled and the solid product was collected on afilter and then treated with sodium hydroxide solution to generate thefree base which was recrystallized from aqueous methanol to give a solidof M.P. 185l87, yield 30.0 g.

Analysis.Calcd. for C H ClN O N, 13.1. Found: N, 13.6.

B. 3 [5 (4-PHENYLl-P IPERAZYL) PENTYL] -6CHLORO-2,- 4: (1H,3H)-QUINAZOLINEDIONE DIHYDROCHLORIDE The above solid was dissolved inmethanol and treated with excess dry hydrogen chloride to give aprecipitate of hydro-chloride which was collected and recrystallizedthree times from aqueous methanol, M.P. 226-230", yield 13.0 g.

Analysis.Ca1cd. for C H C1N O '2HCl: N, 11.2; N (basic), 5.61. Found: N,11.2; N (basic), 5.84.

EXAMPLE 17 3- [3-(4-m-chlor0phenyl-1 -piperazyl propyl] -2,4 (1 H ,3Hquinazolinedione monohydrochl'oride :To a boiling solution of1-[3-(o-aminobenzamido)propyl]-4-m-chlorophenylpiperazine, the productof Example 6A, (365 g.) in 2 l. of chlorobenzene was bubbled in a slowstream of phosgene (105 g.) during an hour period and then the reactionmixture was kept at room temperature overnight. It was cooled in anice-water bath and the solid product was collected on a filter, washedwith 2-propanol-ether and the wet cake was recrystallized from a mixtureof 750 ml. of DMF and 2 liters of water. The slightly tan product wasagain recrystallized from a mixture of 500 ml. of acetic acid and 1500ml. of water (charcoal). and the pure product was collected by suction,washed with acetone and dried in an oven at 50, M.P. 240-241", yield 292g. (70.5% based on the amide).

Analysis.-Calcd. for C21H23C1N402'HC1I N (basic), 3.22; HCl, 8.38.Found: N (basic), 3.17; HCl, 8.45.

12 EXAMPLE 1s 4-m-chl0r0phenyl-1-methyl-1- [3-{2,4-di0x0-3 (1H,3H)quinaz0linyl}propyl]piperazinium methosulfate To a hot solution of3-[3-(4m-chlor0phenyl-l-piperazyl)propyl] -2,4(1H,3H)-quinazolinedione(27.6 g., 0.069 mole) in a mixture of acetone ml.) and DMF (100 ml.) wasadded 20 ml. of dimethyl sulfate and the clear solution was refluxed foran hour. The solution was concentrated in vacuo and ethyl acetate-etherwas added to give an oil which soon solidified to give a colorlesssolid. It was collected on a filter, washed with ethyl acetate-ether anddried in air, yield 18.2 g. It was once recrystallized frommethanol-ethyl acetate to give a colorless solid of M.P. 204-206 (dec.),yield 15.3 g.

3280 (N-H), 1725 and 1640 cmr (imide carbonyls), no amide II band.

Analysis.-Calcd. for C H C1N O (CH SO C, 52.3; H, 6.22; N, 10.2. Found:C, 52.6; H, 5.54; N, 10.3.

EXAMPLE 19 3 (3 -m 0rphi0lini0 propyl -2,4 1 H ,3H -quin az0linedi0ne A.N'3- o-AMINO BENZAMIDO PROPYLMORPHOLINE To N-(3-aminopropyl)morpholine(57.6 g., 0.4 mole) was added isatoic anhydride (65.2 g., 0.4 mole) togive a slurry with evolution of heat and carbon dioxide. The reactionmixture was heated on a steam bath for 45 minutes and cooled to roomtemperature. A large excess of ether was added to give a milky solutionfrom which soon deposited a colorless solid on scratching, yield 95.4g., M.P. 98100. Upon dilution of the filtrate with Skelly B another 3.8g. of the product was obtained. The total yield was 99.2 g. A sample wasrecrystallized from acetone-Skelly B to give a colorless solid of M. P.99-101".

Analysis-Calcd. for C I-1 N 0 N(basic), 5.21. Found: N (basic), 5.24(titration).

B. 3- (3-MORPI-IOLINOPROPYL)-2,4(1H,3H)-

QUINAZOLINEDIONE To a boiling solution of the above amine (46.3 g.,0.172 mole) in 250 ml. of chlorobenzene was bubbled in phosgene during a45 minute period with vigorous stirring to give an amber colored gumwhich made stirring difiicult. The reaction mixture was cooled in anice-water bath to give a hard solid mass which was dissolved in hotmethanol, treated with charcoal and diluted with ethyl acetateether togive a light tan sticky syrup which gradually solidified on scratching,yield 52.7 g. It was recrystallized twice from acqueous Z-propanol-ethylacetate and then the free base was obtained by treating it with acqueousammonia, yield 18.2 g., M. P. -168. A sample was recrystallized fromaqueous acetone-DMF to give a colorless solid of MP. 168169.

Analysisr-Calcd. for C H N O N, 14.6. Found: N, 14.7.

C. 3- (MORPHOLINOPROPYL-Zl (1H,3H) QUINAZOLINE- DIONE HYDROCHLORIDE Theabove free base (15.1 g.) was suspended in methanol, saturated with dryhydrogen chloride and diluted with ether to give a colorless solid ofM.P. 242243, yield 14.4 g.

KC] unn.

1720 and 1665 cm.- (imide carbonyls), 1120 cm.- (aliphatic ether), noamide II band.

Analysis.Calcd. for C H N O .HCl: N, 12.9; HCI, 11.3. Found: N,12.8;HCl, 11.4.

13 EXAMPLE 20 3-{3- [1-Methyl-2,3,4,5-tetmhydro-1,4(1H)-benzodiazcpin-4-y l] -prpyl}-2,4(1H,3H -quinaz0linedi0ne A. 1-METHYL-2,3,4,5-TETRAHYDRO-1,4-BENZO-DIAZEPINE N-methyl N phenylethylenediamine (166.2 g., 1.1 mole) wasadded slowly to 250 ml. of 90% formic acid at about Formalin (37%, 90ml.) was added to the solution which was then heated on a steam bath for60 hours. Then the solution was cooled and poured onto ice and madebasic with concentrated sodium hydroxide solution. The free base wastaken up in chloroform and the extract was dried. After removing thesolvent in vacuo the free base was heated in 20% hydrochloric acidovernight. The water was evaporated and the free base was generated withsodium hydroxide solution and then extracted with ether. The extract wasdried the solvent was stripped off and the free base was distilled togive a liquid boiling at 87-93 (0.43 mm.), yield 45 g. (25%Analysis-Calcd. for C H N N (basic), 8.64. Found; N (basic), 8.63.

B. 1-METI-ILY-2,3,4,5-TETRAHYDRO-1,4-BENZO- DIAZEPINE HYDROCHLORIDE Thehydrochloride from above melted at 148152. Analysis.Calcd. for C H N.HCl: N (basic), 7.05; HCl, 18.4. Found: N (basic), 6.96; HCl, 19.3.

C. 4- (3-AMINOPROPYL) -1-METHYL-2,3,4,5-TETRA- HYDRO-1,4-BENZOD IAZEPINEThe above amine (15 g., 0.093 mole) and a-crylonitrile (5.4 g., 0.102mole) in ml. of dry benzene was refluxed for 2 hours. The solvent wasremoved and then the residue was distilled to give 4.5 g. of thestarting amine and 11.5 g. (75% yield) of the nitrile which was reducedwith Raney nickel catalyst in ammonia saturated methanol under 1000 lb.of hydrogen at 100 to give the amine of B.P. 107-114 (0.025 mm.), yield6.4 g. (55% Analysis.Calcd. for C H N N (basic), 6.36. Found: N (basic),6.35.

D. 3-{3 [1 METHYL TETRAHYDRO 1,4(1H) BENZO- DIAZOPIN 4 YLJ-PROPYL}2,4(1H,3H) QUINAZO- LINE DIHYDROCHLORIDE A mixture of the above amine(6.4 g., 0.029 mole) and isatoic anhydride (4.8 g., 0.029 mole) in 25ml. of henzene was refluxed for an hour and then the solvent wasstripped off. The remaining oil was dissolved in 75 ml. of chlorobenzeneand phosgene was bubbled in under reflux during a minute period to givea gummy solid. It solidified on cooling and recrystallized from methanolcontaining hydrogen chloride to give a yellow solid. It was collectedand slurried in hot 2-propanol, yield 7.5 g. (59%), M.P.217218.

Analysis.Calcd. for C H N O 2HCl: N, 12.8; N (basic), 3.20. Found: N,12.8; N (basic), 3.12.

EXAMPLE 21 3-{2- [1-Methyl-2,3,4,5-tetmhydr0-1,4 (1H) -benz0diazepin-4-yl] ethyl }-2,4 (1H,3H)-quiniaz0linedi0we A.4-CYANOMETHYL-1-METHYL-2,3,4,5-TETRAHYDRO- lA-BENZODIAZEPINE To asolution of sodium bisulfite 10.4 g., 0.1 mole) in ml. of water wasadded 8.1 ml. (0.1 mole) of 37% formalin.1-methyl-2,3,4,5-tetrahydro-1,4-benzodiazepine (16.2 g., 0.1 mole) wasadded to the solution and heated an additional 3 hours. The aqueouslayer was separated at 70 for 2 hours. Then 6.5 g. (0.1 mole) ofpotassium cyanide was added and the mixture was heated at 70 for andextracted with ether. The ether extract was added to the organic layerand dried. Distillation gave 15.7 g. (78% yield) of the 4-cyanomethylderivative boiling at 139-144. (0.5 mm.).

14 Analysis.Calcd. for C H N N,21.0 Found: N, 20.7.

B. 4-AMINOETHYIr1-METHYL-2,3,4,5-TETRAHYDRO- 1,4-BENZODIAZEPINE Thecyanomethyl derivative was reduced with Raney nickel catalyst in ammoniasaturated methanol under 1000 lb. of hydrogen at to give the4-aminoethyl compound in 67% yield, 10.7 g., B.P. 113. (0.025 mm.).

Analysis.Calcd. for C H N N (Ibasic), 13.6. Found: N (Ibasic), 13.3.

C. 3 {2 [1 METHYL 2,3,4,5 TETRAHYDRO 1,4011)- BENZODIAZEPIN 4 YLJETHYL}2,4(1H,3H)-QUIN- AZOLIN'EDIONE DIHYDROCHLORIDE MONOMETHA- NOLATE The.above amine (10.5 g., 0.051 mole) and isatoic .anhydride (8.3 g., 0.051mole) were reacted as described before. The product was dissolved inboiling chlorobenzene and treated with phosgene to give a solid whichwas heated in methanol to give a dihydrochloride monomethanolate, yield3.5 g., M.P. 210 (dec.).

Analysis.Calcd. -for C 'H Cl N O N, 12.3; N (basic), 3.08; HCl, 16.1.Found: N, 12.2; -N basic), 3.12; HCl, 16.0.

EXAMPLE 22 A. 3 [3- (4-PHENYL-1-PIPERIDYL) PROPYL]-6 CHLORO-2,4(1H,3H)-QUINAZOLINEDIONE A mixture of 6-chloroisatoic anhydride (39.5g., 0.2 mole) and 4-phenyl-1-3-(3-aminopropyl) piperidine (43.6 g., 0.2mole) and a small amount of dimethylformamide was heated on the steambath for two hours. The solvent was removed in vacuo and the concentratewas dissolved in 250 m1. of hot chlorobenzene. This solution was heatedto boiling and phosgene was slowly bubbled into the stirred solution for2.5 hours. The solid that formed was collected, washed with ether anddried. The solid was suspended in dilute sodium hydroxide and the freebase was extracted with chloroform. The solid that separated from thechloroform layer was collected, washed with water and dried. This solidwas recrystallized from an aqueous methanol solution, M.P. 198-199.5,yield 10.2 g. (14.4%).

Analysis.Calcd. Found: N, 10.70.

B. 3- 3- (4-PHENYL-1-PIPERIDYL) PROPYL 6-CHLORO 2,4 1H,3H-QUINAZOLINEDIONE MALEATE The free base (10 g., 0.026 mole) wassuspended in methanol and a methanol solution of maleic acid (116 g.,0.1 mole) 'was added with heating. The solution that formed was dilutedwith ether to give a white solid which was collected and recrystallized[from a methanol-ethyl acetate-ether solution, yield 10.3 g. (78% M.P.221.5 222.5" (dec.).

Analysis.-Calcd. for C22H24C1N3O2C4H4O4: C, H, 5.45; N, 8.18. Found: C,61.1; H, 5.94; N, 8.08.

EXAMPLE 23 3- [3-(4-p-Chl0r0phenyl-1-piperazyl) propyl] -2,4(1H, 3H)quinazolinedione A. 4- (p-CHLOROPHENYL) 1-[3-(o-AMINOBENZAMIDO) PRO-PYL]PIPERAZINE A mixture of isatoic anhydride (32.6 g., 0.2 mole), 4-(p-chlorophenyl)-1-(3-aminopropyl)piperazine (50.6 g., 0.2 mole) and asmall amount of dimethylformamide was heated on the steam bath for anhour. Acetone was added and the hot solution was diluted with water toform a white solid. This solid was collected and recrystallized fromaqueous dimethylformamide-acetone, yield "64.3 g. (86.3%), M.P.155.5-156.5.

Analysis.Calcd. for C H C1N O: N, 15.0. Found: N, 14.6.

B. 3- [3- (4-DCHLOROPHENYL-l-PIPERAZYL) PROPYL]- 2,4(1H,3H)-QUINAZOLINEDIONE The 4-(p-chlorophenyl) 1 [3-(o-aminobenzamido)-propylJpiperazine (64.3 g., 0.172 mole) was dissolved in 300 ml. ofboiling chlorobenzene. Phosgene was slowly bubbled into the hot stirredsolution for 2.5 hours. The solid that formed on cooling was collected,washed with ether and dried. This solid was suspended in water and madebasic with concentrated ammonium hydroxide. The free base was extractedwith chloroform. The solvent was removed in vacuo and the solidconcentrate was recrystallized twice from aqueousdimethylformamideacetone and once more from acetone-dimethylformamide,yield 12 g. (17.5%), M.P. 228.5230.0.

Analysis.Calcd. for C H ClN O N, 14.1. Found: N, 13.8.

C. 3-[3-(4-p-'CHLOROPHENYL-l-PIPERAZYL)PROPYL]-2,- 4(1I-I,3H)-QUINAZOLINEDIONE- MALEATE A mixture of the free base (11.5 g., 0.00.9mole) and maleic acid g., 0.086 mole) in methanol was heated until asolution was formed. The solution was filtered and diluted with ether toform a white solid. This solid was collected and recrystallized from amethanol-ether solution, yield 13.2 g. (88.7%), M.P. 195197 (dec.).

Analysis.Calcd. for C H Cl N O -C H O N, 10.9; N (basic), 2.72. Found:N, 10.7; N (basic), 2.73.

EXAMPLE 24 A. 3- 3- (4-p-CHLOROPHENYL-l-PIPERAZYL) PROPYL -6--CHLORO-2,4 (1H,3H) -QUINAZOLINEDIONE To 24.6 g. (0.1 mole) of4-p-chlorophenyl-1-(3-aminopropyl)piperazine was added 22.4 g. (0.1mole) of 6- chloroisatoic anhydride. The mixture was heated for twohours in a wax bath at ISO-200. The melt was then cooled and methanolwas added to the mix-ture. A solid was obtained which was filtered anddried. Without any further purification the material was dissolved inhot chlorobenzene and phosgene was bubbled into the reaction mixture fortwo hours while the solution was refluxing and being stirred. A solidprecipitated while the reaction was still hot; The material was filteredand treated with a mixture of chloroform and ammonium hydroxide. A solidfree base was obtained which was filtered and dried. The free base wasrecrystallized twice from aqueous DMF, yield 25 g., M.P. 25 9-26 2.

Analysis.--Calcd. for C 'H Cl N O N (basic), 3.24. Found: N (basic),3.25.

B. 3-[3 (4-p-CHLOROPHENYL-LPIPERAZYL)PROPYL]-6-CHLORO-ZA(1H,3H)-QUINAZOLINEDIONE MALEATE EXAMPLE 25 A. 3- [3-(4-m-CHLOROPHENYL-1-PIPERAZYL)PROPYL] -6- CHLORO-'2,4(1H,3H)-QUINAZOLINEDIONE A solution of 23.7 g. (0.12 mole) of 6-chloroisatoicanhydride and 30 g. (0.12 mole) of 4-m-chlorophenyl-1-(3-aminopropyl)piperazine in DMF was heated on the steam bath for thirtyminutes. The reaction mixture was then cooled and diluted with water. Asolid was ob tained which was filtered and dried. Without any furtherpurification the material was dissolved in hot chlorobenzene andphosgene was bubbled into the reaction mixture for two hours while themixture was refluxing and being The solution was stirred. The solutionwas then cooled and a precipitate was obtained which was filtered andtreated with a solution of cholorform and ammonium hydroxide. Thecholoroform layer was removed and evaporated in vacuo. A solid wasobtained which was recrystallized twice from a chloroform-methanolsolution, yield 17.6 g., M.P. 198 199.

Analysis.-Calcd. for C H Cl N O N(basic), 3.24. Found: N(basic), 3.21.B. 3- 3- (4-II1-CHLOROPHENYL-LPIPERAZYL) PROPYL] 6-CHLORO-2,4(1H,3H)-Q'UINAZOLINEDIONE MALEATE The maleate salt wasprepared by dissolving 17.6 g. (0.04 mole) of the free base in methanoland adding 4.64 g. (0.04 mole) of maleic acid. After heating the mixtureon the steam bath for a few minutes, the salt precipitated from thesolution. It was filtered and recrystallized twice from an aqueousmethanol solution, yield 14 g., M.P. 223225.

Analysis.-Calcd. for C H Cl N O N(basic), 2.55; N(total), 10.21. Found:N(basic), 2.50; N(total), 10.25.

EXAMPLE 26 A. 3 [4- 4 PHENYL-1-PIPERAZYL) BUTYL] -6-CHLORO- 2,4- (1H,3H)-QUINAZOLINEDIONE To 30 g. (0.13 mole) of4-phenyl-1-(4-aminobutyl)piperazine in ml. of DMF was added 25.7 g.(0.13 mole) of 6-chloroisatoic anhydride and the mixture was heated onthe steam bath for thirty minutes. Water was then added and aprecipitate was obtained which was filtered and dried. The solid wasthen dissolved in hot chlorobenzene and phosgene was bubbled into themixture for one hour while the solution was refluxing and being stirred.After cooling the solution a solid was obtained which was filtered andthen treated with a chloroform-ammonium hydroxide mixture to obtain thefree base which was recrystallized from a chloroform-ether mixturetwice, yield 33 g., M.P. 205-210".

Analysis.Calcd. for C H ClN O N(basic), 3.40. Found: N(basic), 3.66.

B. 3-[4-( L-PHENYL-l-PIPERAZYL)BUTYL]-6-CHLORO-2,4(1H,3H)-QUINAZOLINEDIONE MALEATE The maleate salt was prepared bysuspending 33 g. (0.08 mole) of the free base in methanol and adding9.28 g. (0.08 mole) of maleic acid. The mixture was heated for fifteenminutes and a precipitate was obtained which was filtered andrecrystallized from a methanol-chloroform-ether mixture, yield 15 g.,M.P. 220-222".

Analysis.-Calcd. for C H ClN O N(basic), 2.65; N(total), 10.59. Found;N(basic), 2.69; N(total), 10.39.

EXAMPLE 27 A. 3-[2-(4-PHENYL-1-PIPERAZYL)ETHYL]-6-CHLORO-2,4(1H,3H)-QUINAZOLINEDIONE To 17.9 g. (0.09 mole) of4-phenyl-1-(2-aminoethyl)piperazine in approximately ml. of DMF wasadded 17.8 g. (0.09 mole) of 6-chloroisatoic anhydride and the mixturewas heated on the steam bath for thirty minutes. Water was then added toprecipitate the amide which was filtered and dried. The crude amide wasdissolved into hot chlorobenzene and p-hosgene was bubbled into themixture for one hour while the solution was refluxing and being stirred.After cooling the reaction mixture a solid was obtained which wasfiltered and treated with a mixture of chloroform and ammonium hydroxideto obtain the free base. The layers were separated and the chloroformwas evaporated in vacuo. The residue which was obtained wasrecrystallized from methanol three times, yield 18 g., M.P. 251-253".

Analysis.-Calcd. for C H ClN O N(basic), 3.64. Found: N(basic), 3.64.

B. 3- 2- (4-PHENYL-l-PIPERAZYL ETHYL] 6-CHLORO- 2,4 (1H,3H-QUINAZOLI-NEDIONE MALEATE i The maleate salt was prepared by suspending18 g. (0.46 mole) of the free base in methanol and adding 5.3 g. (0.046mole) of maleic acid. The salt precipitated almost immediately and wasrecrystallized from a methanolchloroform-ether mixture three times,yield 8.5 g., M.P. 230231.

' Analysis.Calcd. for C H ClN O N(total), 11.39; N(basic), 2.80. Found:N(t-otal), 11.19, N(basic), 2.86.

EXAMPLE 28 A. 3-(3-MORPHOLINOPROPYL)-6 CHLORO-2,4 (1H,3II)

4 QUINAZOLINEDIONE To 30 g. (0.21 mole) of N-(3-aminopropyl)morpholinein approximately 100 ml. of DMF was added 41.5 g. (0.21 mole) of6-chloroisatoic anhydride. The mixture was [heated for thirty minutes onthe steam bath. Water was added to precipitate the amide. The solid wasfiltered and dried. The crude material was then dissolved in hotchlorobenzene and phosgene was bubbled into the reaction mixture for onehour while the solution was refluxing and being stirred. After coolingthe mixture a solid was obtained which was filtered and treated with achloroform-ammonium hydroxide mixture. The chloroform layer was removedand the chloroform evaporated in vacuo. The residue was recrystallizedfrom a chloroform-ether mixture three times, yield 41 'g. M.P. 173- 174.

Analysis.-Calcd. for C H ClN O N(basic), 4.34. Found: N(basic), 4.33.

B. 3-(3-MORPHOLINOPROPYL)-61C'HLORO-2,4(1H,3H)-

QUINAZOLINEDIONE MALEATE The maleate salt was prepared by suspending the41 g. (0.135 mole) of free base in methanol and adding 15.6 g. (0.135mole) of maleic acid. The mixture was heated for a few minutes on thesteam bath and after cooling a precipitate was obtained which wasfiltered and recrystallized from a methanol-ether mixture three times,yield 25 g., M.P. 181-184. 7

Analysis.-Calcd. for C H ClN O N (total), 9.57; N (basic), 319. Found: N(total), 9.55; N (basic) 3.23.

EXAMPLE 29 A. 3- 2- 4-m-CHLOROPHENYL-l-PIPERAZYL) ETHYL] -6- CHLORO-ZA(1H,3H) -QUINAZOLI NEDIONE To 23.7 g. (0.12 mole) of 6-chloroisatoicanhydride was added 25 g. (0.12 mole) of 4-m-chloroph'enyl-1-2(2-aminoethyl)piperazine in 150 ml. of DMF. The mixture was heated on thesteam bath for 30 minutes and water was then added to precipitate theamide. The amide was filtered and dried and then without any furtherpurification dissolved in hot chlorobenbene. Phosgene was bubbled intothe mixture while the solution was refiuxing and being stirred for 2hours. A brown oily residue separated while the mixture was still hot.Upon cooling the oil solidified and was filtered by suction. The solidwas treated with a solution of chloroform and ammonium hydroxide toobtain the free base. The chloroform layer was separated and thechloroform was evaporated in vacuo. A residue was isolated which wasrecrystallized three times from a methanol-DMF-water mixture, yield 9.0g., M.P. 228-230". I

Analysis.Calcd. for C H Cl N O N (basic), 3.34. Found: N (basic), 3.36.

B. 3- 2- (4-m-CHLOROPHENYL-1-PIPERAZYL E'IHYL] -6- CHLORO-2,4=(1H,3H)-QUINAZOLINEDIONE MALEATE The maleate salt was prepared by suspendingthe free base in methanol and adding 2.5 g. (0.021 mole) of maleic acid.The mixture was heated on the steam bath for 15 minutes. A solid wasobtained which was filtered and recrystallized twice with charcoal froma methanol- DMF-ether mixture, M.P. 220-222.

Analysis.-Calcd. for C H Cl N O N (basic), 2.2.6;

18 N (total), 10.46. Found: N (basic), 2.65; N (total), 10.28.

EXAMPLE 3O 3-[4-(4-m-chl0r0phenyl-1-piperazyl) butyl] -2,4 (1H,3H)quinazolinedione hydrochloride A mixture of1-(4-aminobutyl)-4-m-chlorophenylpiperazine (53.5 g., 0.2 mole) andisatoic anhydride (32.6 g., 0.2 mole) was heated on a steam bathovernight after the initial reaction had subsided. The amber syrup wasdissolved in 250 ml. of chlorozenzene. A slow stream of phosgene wasbubbled in during a 60 minute period at the boiling point of the solventto give a tan solid which came out from the hot reaction mixture. It wascooled in an ice-water bath and the solid was collected by suction,washed with ethyl acetate and dried in vacuo in a desiccator, yi'eld132.2 g., M.P. 230-238 (dec.) It was once recrystallized from aqueousmethanol-ethyl acetate to give a crystalline solid of M.P. 243-245,yield 51.2 g.

1710 and 1660 cm.- (illide carbonyls), no amide II band.

Analysis.Calcd. for C H Cl N O N, 12.5; HCl, 8.13. Found: N, 12.2; HCl,8.12.

EXAMPLE 31 3- [3- (4- phenyl-1-piperazyl) propyl] -6-nitr0-2,4(1H,3H)quinazolinedione A. N- [3- (4-PHENYL-1-PIPERAZYL) PROPYL -N'- (2-'CARBOXY-l-NITROPHENYL) UREA The filtrate was concentrated by heating ona hot plate and excess water was added to give a dark oil which slowlysolidified on scratching. The yield was 97.0 g., (77.8%) M.P. 143-145with softening at 138". It was dissolved in hot DMF and added to a largeexcess of water to give a yellow powder of M.P. 140-144". It was againrecrystallized to give an analytical sample of M.P. 141-144".

CHCI max.

3500 and 3330 cm. (NH and NH), 1645 cm.- (amide carbonyl), 1550 cm.-(amide II), 1505 and 1330 cm. (N0

Analysis.Calcd for C H N O N, 18.30; (basic), 3.66. Found: N, 18.23; N,(basic), 3.60.

C. 3- [3- (l-PHENYL-l-PIPERAZYL) PROPYLPG-NITRO- I2,4(1H,3H)-QUINAZOLINEDIONE Method 1: To a boiling solution of1-[3-(2"-amino-5'- nitrobenzamido)-propyl]-4-phenylpiperazine (95.2 g.,0.249 mole) from B in 400 ml. of chlorobenzene was bubbled in a slowstream of phosgene during a minute period to give a tan solid. Thereaction mixture was kept at room temperature overnight and the solidwas collected on a filter, yield 112.5 g., M.P. 245-250 (dec.) withsoftening at 210. It was suspended in water and made basic with aqueousammonia to give a yellowish brown solid, yield 99.1 g., M.P. 170-219with softening at It was recrystallized twice from aqueous 19methanol-DMF to give a deep yellow solid of M.P. 208- 210, yield 50.0g.,

(EH01; "max. 1725 and 1670 cm? (imide carbonyls), 1540 and 1340 cm:- (N

Analysis.-Calcd. for C H N O N, 17.14. Found: N, 17.26.

Method 2: N-[3-(4-phenyl-1-piperazyl)propyl]-N'-(2-carboxy-4-nitrophenyl)urea from A (13.4 g.) was recrystallized twicefrom aqueous DMF-methanol to give a yellow solid of M.P. 208210, yield8.0 g. Mixed M.P. with the product by method 1 was not depressed. TheLR. spectra were identical.

Analysis.--Calcd. for C H N O N, 17.14. Found: N, 17.07.

N [3 (4 phenyl 1 piperazyD-propyl] N (2- carboxy-4 nitrophenyl)-urea,isolated in Example 31 as a by-product of the reaction between6-nitroisatoic anhydride and 1-(3-aminopropyl)-4-phenylpiperazine,provides another useful synthetic route to the novel quinazolinedionesof this invention. As shown in the example heating of the correspondingurea derivative with elimination of water produces the quinazolinedionein good yield.

EXAMPLE 32 3- [3- (4-phenyl-1 -piperazyl propyl] -6-acetamido-2,4- (1 H,3H -quinazolinedi0ne A. 313- (4-PHENYL-1-PIPERAZYL) PROPYL] -6-AMINO-2,4 (1H,3H) -QUINAZOLINEDIONE 3 [3- (4 phenyl 1 piperazyl)propyl] 6nitro- 2,4(1H,3H)-quinazolinedione (50.0 g., 0.123 mole), the compoundof Example 31, was hydrogenated with 10 g. of palladium on charcoal (5%by Weight) in 400 ml. of glacial acetic acid under 50 lb. of initialhydrogen pressure at room temperature. The calculated amount of hydrogenwas taken up in 30 min. The catalyst was removed and the solvent wasevaporatedofi in vacuo to leave a brown viscous syrup which was treatedwith liquid ammonia to give a solid of M.P. 229-235, yield 46.9 g. Itwas once recrystallized from aqueous methanol- DMF (carbon) to give abrown powder of M.P. 234-238", yield 37.9 g. The amino derivative isunstable in air and the salt became dark during purification.

B. 3-[3-(4-PHENYL-1-PIPERAZYL)PROPYL]-6-ACETA- MIDO-2,4 (1H,3H-QUINAZOLINEDIONE MALEATE The above amino derivative (30.2 g.) washydrogenated again in a mixture of glacial acetic acid (200 ml.) andacetic anhydride (50 ml.) with 5 g. of palladium on carbon (5% byweight) to reduce any oxidized material. The product was obtained asdescribed above; yield 27.2 g., M.P. 258-262" (softening at 252). It wasrecrystallized from aqueous methanol-DMF to give a tan powder of M.P.257261 (dec.), yield-18.1 g. It was suspended in methanol and maleicacid (5.8 g., 0.05 mole) was added to give a slurry which was dissolvedin aqueous methanol- DMF, treated with charcoal and concentrated. ,Itwas boiled down with ethyl acetate to give a pure maleate of M.P.245-246v (dec.), yield 19.7 g.

1710 and 1650 cm. (imide carbonyls), 1650 cmr (AoNH).

Analysis.-Calcd. for C23H27N5O3.C4H404: C, H,

5.77; N, 13.0. Found: C, 60.0; H, 5.56; N, 13.0.

EXAMPLE 33 mole) and a small amount of dimethylformamide 'was heated onthe steam bath for one hour. The reaction product was dissolved in hotacetone and diluted with water to form a solid, which was collected andrecrystallized from an aqueous acetone solution, yield 40 g. (55.8%),M.P. 125.5-1265.

Analysis.-Calcd. for C H ClN O: N, 15.62. Found: N, 16.08. I

B. 3- ['2- (4-m-CHLOROPHENYL-l-PIPERAZYL) ETHYL] 2,4(1H,3H)-QUINAZOLINEDIONE A suspension of4-m-ehlorophenyl-1-[2-(o-aminobenzamido)-ethyl]piperazine (40 g., 0.111mole) in 200 ml. of chlorobenzene was heated to boiling and phosgene wasslowly bubbled into the solution for 45 minutes. The solid that formedwas collected, washed with ether and dried. The solid was shaken inchloroform and ammonium hydroxide solution and the chloroform layer wascollected and concentrated in vacuo to a solid. This solid was twicerecrystallized from an aqueous DMF-acetone solution, yield, 13 g.(30.5%), M.P. 212.5214.5.

Analysis.-Calcd. for C2OH21CIN4IOZ2 N, 14.56. Found: N, 14.54.

C. 3-[2- 4-m-CHLOROPHENYL-l-PIPERAZYL) ETHYL] -2,4- (1H,3H)-QUINAZOLINEDIONE MALEATE A suspension of this free base (13 g., 0.034mole) and maleic acid (8 g., 0.07 mole) in methanol were heated to forma solution that immediately solidified. Water was added and the hotsolution was filtered. The filtrate was diluted with ether and cooled toform a crystalline solid. This solid was collected, washed with etherand dried, yield, 12.5 g. (74%), M.P. 21-0.5211.5 v(dec.).

Analysis.Calcd. for C2oH21ClN402.C4LI'I404: N, N (basic), 2.80. Found:N, 11.25; N (basic), 2.89.

In summary this invention provides a series of novel quinazolinedioneswhich have useful sedative and antiinflammatory properties andconvenient methods for their preparation. These compounds correspond tothe general formula:

wherein R represents one or more groups such as hydrogen, halogen, loweralkyl, lower alkoxy, nitro and amino including acyl-amino; n equals 0 to6 inclusive; and R represents di-lower alkylamino or a heterocyclicradical such as piperazyl, pyridyl, piperidyl, piperazinium,morpholinyl, benzodiazepinyl and various substituted derivatives ofthese and other nitrogen containing heterocycles. A preferred sub-groupof these compounds includes dilower alkylamino, piperazyl, phenylsubstituted piperazyl, substituted-phenyl substituted piperazyl,phenalkyl substituted piperazyl, pyridyl, piperadyl, phenyl substitutedpiperidyl, piperazinium, phenyl substituted piperazinium,substituted-phenyl substituted pip'erazinium, morpholinyl,benzodiazepinyl and substituted benzodiazepinyl. The varioussubstituents may be those listed for R and may also include any otherradical commonly encountered in organic chemistry. An especiallypreferred sub-group of such compounds are those which contain thepiperazyl radical. I

These compounds are usually provided in the form of their salts forreasons of stability and solubility. Especially important are thosesalts such as the hydrochloride and maleate and other,pharmacologicallyacceptable salts.

21 What is claimed is: 1. A compound selected from the group consistingof a compound of the formula R f H wherein R is a member selected fromthe group consisting of hydrogen, chloro, nitro and lower alkanoylamino; n is a number from to 6 inclusive; and R is a member selectedfrom the group consisting of piperazyl, 4-phenyll-piperazyl;4-(chlorophenyl)-1 piperazyl; 4-phenyl lower alkyl -1-piperazyl;pyridyl; l-piperidyl; 4-phenyl-1-piperi dyl; piperazinium methosulfate;4-phenyl piperazinium rnethosulfate; 4-phenyl-1 loweralkyl-l-piperazinium methosulfate; 4-chlorophenyl-1 loweralkyl-l-piperazinium; morpholino; 2,3,4,5-tetrahydro1,4(1H)benzodiazepin-4-yl; and 2,3,4,5-tetrahydro-1 lower alkyl-l,4(1H)benzodiazepin-4-yl; and pharmacologically acceptable acid additionssalts thereof.

2. 3 [2-(4-phenyl-l-piperazy)ethyl]-2,4(1H, 3H) -quinazolinedione.

3. 3 3 (4-phenyl-1-piperazy1)ethyl]-2,4(1H, 3H)- quinazolinedione.

References Cited by the Examiner UNITED STATES PATENTS 2,680,741 6/1954Gilbert 260260 2,688,020 8/1954 MacKay et al 260260 3,095,443 6/ 1963Cavallini et a1 260-471 3,096,373 7/1963 Kirchner 260-558 3,118,9301/1964 Sisido et a1. 260-47] 3,161,678 12/ 1964 Thominet 260$ OTHERREFERENCES Burger: Medicinal Chemistry, 2nd ed., New York, IntersciencePublishers, Inc., 1960, p. 42.

Elderfield: Heterocyclic Compounds, vol. 6, New York, John Wiley andSons, Inc., 1957, p. 347.

Kunckell: Berichte, vol. 43, 1910, pp. 1021-1024.

ALEX MAZEL, Primary Examiner.

NICHOLAS S. RIZZO, HENRY R. JILES, Examiners. J. W. ADAMS, M. OBRIEN,Assistant Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,274,194 September 20, 1966 Shin Hayao It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 3, line 5, for "wits" read with column 4, line 68, for "33330 cm.read 3330 cm.' column 9, line 31, for "4.72; MCI," read 4.72; HCl,column 13, line 23, for "l-METHLY" read l-METHYL column 13, line 68,after "heated" insert at 70 for Zhours. Then 6.5 g. [0.1 mole) ofpotassium cyanide was added and the mixture was heated at 70 for lines70 and 71, strike out "at 70 for 2 hours. Then 6.5 g. (0.1 mole) ofpotassium cyanide was added and the mixture was heated at 70 for" column17, line 47, for "4-m-ch1orophenyl12(2-" read 4-m-chloropheny1-l-(Z-column 18, line 21, for "(illide carbonyls)" read (imide carbonyls) line61, for "18.30; (N" read 18.30; N line 74,

for "M.P. l70219" read M.P. 170-2l0 Signed and sealed this 29th day ofAugust 1967.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. A COMPOUND OF SELECTED FROM THE GROUP CONSISTING OF METHOSULFATE;4-CHLOROPHENYL-1 LOWER ALKYL-1-PIPERAZINIA COMPOUND OF THE FORMULA